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Probing the sensitivity of autoantibody production to B cell depletion by Rituximab

Ferraro, Alastair James (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

Rituximab, a monoclonal antibody directed against the human CD20 antigen, causes profound depletion of all B cells. When used in patients with autoimmune disease, IgG autoantibody titres often fall whilst serum IgG anti-tetanus toxoid antibody titres are unaffected. Antibodies of both these antibody specificities have features associated with production by long-lived CD20- plasma cells that should be resistant to Rituximab. Reasons for the differential loss of these apparently similar types of antibody were investigated. Initial experiments established multiplexed bead assays to measure, in parallel, serum titres of multiple antibody specificities. Paired acute and convalescent sera, from 11 patients treated with Rituximab for Wegener‟s granulomatosis, were then studied. During 5 months after treatment, and following clinical remission, IgG anti-Proteinase 3 autoantibody titres fell gradually. All other measured antibody titres remained little changed. These findings favour the hypothesis that autoantibody producing plasma cells are sustained by disease related inflammation. Subsequent experimental studies support a wider hypothesis -that inflamed sites can support increased plasma cell numbers. In the prolific humoral response of QM mice to immunisation with NP-Ficoll, concurrent infection with attenuated Salmonella enterica serovar Typhimurium increases splenic capacity to support plasma cells. The enhanced support may reflect locally increased IL-6 production.

Type of Work:Ph.D. thesis.
Supervisor(s):Maclennan, Ian and Savage, Caroline
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of immunity and infection
Subjects:RA Public aspects of medicine
Institution:University of Birmingham
ID Code:691
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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